Finding a genetic connection: Diseases and defects in cattle

It's no secret that genes play an important role in genetic abnormalities in cattle, but could a gene be responsible for resistance or tolerance to diseases? That's what Agricultural Research Service (ARS) researchers are trying to find out.

At the ARS Roman L. Hruska U.S. Meat Animal Research Center (USMARC) in Clay Center, Neb., scientists have identified a chromosome that sheds light on a genetic connection to overall animal health. They've also found the gene mutation that causes a deadly bone disorder in Red Angus cattle and developed a test that detects carriers of the disease.

Searching for the Origin of Diseases

Instead of looking at just one disease, scientists combined the three most prevalent bacterial diseases pinkeye, foot rot and bovine respiratory disease that affect feedlot cattle to represent overall pathogenic disease incidence.

Bovine respiratory disease, which is responsible for 75 percent of feedlot morbidity and about 70 percent of all deaths, is the most costly feedlot disease in the United States. Losses are estimated at more than $1 billion each year. Pinkeye can affect up to 80 percent of a herd and costs an estimated $150 million, while foot rot, which causes lameness, can cost dairy producers as much as $350 per animal. Cattle affected by any one of these diseases suffer from lower weight gains, lower feed efficiency, decreased milk production and lower reproduction performance.

"Putting all three diseases together allows us to look at resistance to multiple diseases," says Eduardo Casas, research leader of the Ruminant Diseases and Immunology Research Unit at the ARS National Animal Disease Center in Ames, Iowa, and a former USMARC geneticist. "This gives us a better chance at finding genetic markers associated with conferring resistance or tolerance to diseases."

In previous research involving offspring affected by pinkeye only, Casas found that regions on chromosomes 1 and 20 held genes that influence the presence of bacteria. However, no strong linkage to quantitative trait loci (QTL) which are genetic locations on the chromosome was identified. In his second study that combined pinkeye with foot rot and bovine respiratory disease, Casas found QTL on bovine chromosome 20 associated with the diseases.

Four half-sibling families were produced to detect QTL associated with combined incidences of the three diseases. Brahman-Hereford, Brahman-Angus (BA), Piedmontese-Angus and Belgian Blue-MARC III (part Red Poll, Pinzgauer, Hereford, and Angus) bulls were mated with other breeds. Of the more than 1,150 calves bred, 240 had one or more of the diseases. DNA analyses of the calves revealed QTL for disease activity.

"One of the most interesting things about the genetic marker chromosome 20 is that it is in very close proximity of other markers related to other diseases, such as Johne's disease and bovine viral diarrhea," Casas says. "That particular region may have a significant effect on the general health of animals."

Identifying responsible genetic markers would provide an opportunity for effective crossbreeding to produce animals with increased disease tolerance, he says. This also would greatly reduce the economic impact of diseases to the cattle industry.

Uncovering the Gene Mutation Behind a Bone Disease

While Casas searched for a genetic link to various diseases, USMARC chemist Timothy Smith and geneticist Tara McDaneld were trying to identify the gene mutation responsible for a rare and deadly bone disease that had resurfaced in Red Angus cattle.

Marble bone disease, also known as osteopetrosis, had not been seen in the United States since the 1960s, when it appeared in Black Angus. A deadly birth defect that affects humans, cattle and other animals, osteopetrosis causes abnormal development of the brain cavity and bone marrow cavity, leading to overly dense, brittle bones that shatter easily.

"Calves have to inherit the mutation from both parents," Smith says. In the Northern Plains, there was significant concern because the Red Angus breed's most popular bull was related to some of the animals that had produced osteopetrosis-affected calves.

"A lot of calves were indirectly linked to that bull, so breeders wanted to make sure that they weren't continuously putting the DNA for the disease into their herds," McDaneld adds.

Smith, McDaneld and geneticist Tad Sonstegard at ARS' Henry A. Wallace Beltsville Agricultural Research Center in Beltsville, Md. collaborated with researchers at several universities, including the University of Illinois and the Red Angus Association of America (RAAA) to identify the gene mutation responsible for osteopetrosis and to develop a diagnostic test for the disease.

Samples of DNA from affected calves and their carrier parents were compared to unaffected animals. A search of the genomes of all calves was conducted to find chromosomal segments common to the affected animals, but different from the normal animals. The Illumina Bovine SNP50 BeadChip, a glass slide containing thousands of DNA markers, was used to identify suspect genes.

"We were looking for regions from the affected calves where the chromosome was similar on both the mother's copy and the father's copy," Sonstegard says.

Scientists found this region on cattle chromosome 4, which contains SLC4A2 a gene essential for proper osteoclast maintenance and function, McDaneld says. Osteoclasts are cells that break down old bone during bone development and remodeling.

Some of the SLC4A2 genetic material in the osteopetrosis-affected calves had been deleted, she says. This was a new discovery in cattle.

Within months, scientists were able to develop a polymerase chain reaction (PCR) test and have it available to breeders in less than a year. They also determined that the popular bull was not a carrier of osteopetrosis.